Cell and Tissue Responses to Extracellular Matrix Fibronectin
Fibronectin is distributed in extracellular matrices throughout the body. We know that the ECM form of fibronectin stimulates cell spreading, growth, contraction, and migration by a mechanism that utilizes a cryptic heparin-binding site in the first type III module of fibronectin (FNIII-1). We also know that the matricryptic site is exposed in vivo during skeletal muscle contraction and initiates signals that stimulate vasodilation and increased blood flow to tissues. Using both in vitro and in vivo approaches, we are currently investigating factors and events that control the exposure of the matricryptic FNIII-1 site. We are also performing studies to identify the receptor and downstream signaling molecules that mediate the effects of ECM fibronectin on cell function.
Fibronectin Matrix Remodeling in Chronic Diseases
Fibronectin matrix polymerization in tissues is normally tightly-regulated. This ensures that fibronectin remains soluble in the plasma and is converted into insoluble, biologically-active fibrils only at appropriate sites. Inappropriate fibronectin matrix deposition occurs in several pathological conditions associated with tissue remodeling, including atherosclerosis, hypertrophic scar formation, pulmonary and renal fibrosis, and asthma. In contrast, reduced fibronectin matrix deposition is associated with abnormal wound repair. We are currently asking questions about how chronic conditions such as diabetes and emphysema affect ECM remodeling and fibronectin function in tissues. Our questions include: How does chronic exposure to cigarette smoke affect extracellular matrix remodeling in the lung? Is fibronectin matrix assembly essential for normal wound repair and is this process dysregulated in chronic diabetic wounds? Can we develop methods to promote normal matrix assembly in damaged tissues?
Tissue Engineering and Regenerative Medicine
As with tissue repair, successful development of engineered cell or tissue analogs requires the re-creation of a biologically active extracellular matrix. The cellular mechanisms and structural requirements that control the assembly of the ECM are not well understood. As such, attempts to reconstitute this complex environment in vitro in order to create functional tissue analogs have met with limited success. Our work in this area focuses on developing novel ECM-based therapies to promote tissue regeneration and accelerate wound repair. These approaches include engineering small molecule analogs of extracellular matrix proteins for topical application to wounds and the use of therapeutic ultrasound to up-regulate extracellular matrix function in engineered tissue constructs.